Publications by authors named "Takaaki Ito"

261 Publications

Anatomical resection is useful for the treatment of primary solitary hepatocellular carcinoma with predicted microscopic vessel invasion and/or intrahepatic metastasis.

Surg Today 2021 Feb 9. Epub 2021 Feb 9.

Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center Hospital, 1007, Shimo-Nagakubo, Sunto-Nagaizumi, Shizuoka, 411-8777, Japan.

Purpose: The aim of this study was to evaluate anatomical resection (AR) versus non-AR for primary solitary hepatocellular carcinoma (HCC) with predicted microscopic vessel invasion (MVI) and/or microscopic intrahepatic metastasis (MIM).

Methods: This retrospective study included 358 patients who underwent hepatectomy and had no evidence of MVI and/or MIM on preoperative imaging. The predictors of MVI and/or MIM were identified. The AR group (n = 222) and the non-AR group (n = 136) were classified by number of risk factor, and the survival rates were compared.

Results: Microscopic vessel invasion and/or MIM were identified in 81 (22.6%) patients. A multivariate analysis showed that high des-gamma-carboxy prothrombin concentration [odds ratio (OR) 3.35], large tumor size (OR 3.16), and high aspartate aminotransferase concentration (OR 2.13) were significant predictors. The 5-year overall survival (OS) in the patients with zero, one, two, and three risk factors were 97.4%, 73.5%, 71.5%, and 65.5%, respectively. The OS of AR is superior to that of non-AR only in patients with one or two risk factors.

Conclusion: The present findings suggest that AR should be performed for patients with one or two risk factors, and that AR may prevent recurrence, as these patients are at risk of having MVI and/or MIM.
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http://dx.doi.org/10.1007/s00595-021-02237-1DOI Listing
February 2021

Clinical Significance of Preoperative Albumin-Bilirubin Grade in Pancreatic Cancer.

Ann Surg Oncol 2021 Jan 23. Epub 2021 Jan 23.

Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Sunto-Nagaizumi, Shizuoka, Japan.

Background: No study has clarified the clinical significance of albumin-bilirubin (ALBI) grade in a large cohort of pancreatic cancer patients.

Methods: A total of 1006 consecutive patients diagnosed with pancreatic cancer and deemed eligible for surgical resection were analyzed. The ALBI score was calculated as: ALBI score = (log bilirubin [µmol/L] × 0.66) + (albumin [g/L]  × - 0.0852). ALBI grade was assigned as grade 1, 2a, 2b, and 3. ALBI grade 1 was assigned to the ALBI low group (N = 566), and grades 2a, 2b, and 3 to the ALBI high group (N = 440).

Results: The primary lesion could not be resected in 129 patients. Among all patients, overall survival (OS) was significantly worse in the ALBI high group than in the ALBI low group (P = 0.024). Overall, 877 patients underwent pancreatectomy. In these patients, the ALBI high group was associated with high CA19-9 level (P < 0.001), lower morbidity rate (P < 0.001), and pancreatic head tumor (P = 0.001). Patients' OS after resection was significantly worse in the ALBI high group than in the ALBI low group (P < 0.001). Cox proportional hazard analysis revealed ALBI grade as an independent predictor for prognosis (hazard ratio, 1.33; P = 0.015). Even in the CA19-9 negative patients, OS was significantly worse in the ALBI high group than in the ALBI low group (P = 0.046).

Conclusions: The ALBI grade is a clinically useful predictor for prognosis in pancreatic cancer patients.
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http://dx.doi.org/10.1245/s10434-021-09593-9DOI Listing
January 2021

[Impact of Aperture Shape Controller on Knowledge-based VMAT Planning of Prostate Cancer].

Nihon Hoshasen Gijutsu Gakkai Zasshi 2021 ;77(1):23-31

Department of Radiological Technology, Kobe City Nishi-Kobe Medical Center.

Purpose: Knowledge-based planning (KBP) has disadvantages of high monitor unit (MU) and complex multi-leaf collimator (MLC) motion. We investigated the optimal aperture shape controller (ASC) level for the KBP to reduce these factors in volumetric modulated arc therapy (VMAT) for prostate cancer.

Methods: The KBP model was created based on 51 clinical plans (CPs) of patients who underwent the VMAT for prostate cancer. Another 10 CPs were selected randomly, and the KBPs with/without ASC, changed stepwise from very low (KBP-VL) to very high (KBP-VH), were performed with a single auto-optimization. The parameters of dose-volume histograms (DVHs) and MLC performance metrics were evaluated. We obtained the modulation complexity score for VMAT (MCSv), closed leaf score (CLS), small aperture score (SAS), leaf travel (LT), and total MU.

Results: The ASC did not affect the DVH parameters negatively. The following comparisons of MLC performance were obtained (KBP vs. KBP-VL vs. KBP-VH, respectively): 0.25 vs. 0.27 vs. 0.30 (MCSv), 0.19 vs. 0.18 vs. 0.16 (CLS), 0.50 vs. 0.45 vs. 0.40 (SAS), 0.73 vs. 0.68 vs. 0.63 (SAS), 768.35 mm vs. 671.50 mm vs. 551.32 mm (LT), and 672.87 vs. 642.36 vs. 607.59 (MU). There were significant differences between KBP and KBP-VH for MCSv and LT (p<0.05).

Conclusions: The KBP using an ASC set to the very high level could reduce the complexity of MLC motion significantly more without deterioration of the DVH parameters compared with the KBP in VMAT for prostate cancer.
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http://dx.doi.org/10.6009/jjrt.2021_JSRT_77.1.23DOI Listing
January 2021

Clinical Implication of Node-negative Resectable Pancreatic Cancer.

Ann Surg Oncol 2021 Apr 15;28(4):2257-2264. Epub 2021 Jan 15.

Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan.

Background: Lymph node metastasis is one of the strongest prognostic factors of pancreatic cancer. However, the clinical implication of pathologically node-negative pancreatic cancer (pN0-PC) has not been fully investigated.

Methods: Patients who underwent surgical resection for radiologically resectable pancreatic cancer between 2002 and 2018 were included in this study. A clinicopathological examination focusing on pN0-PC was performed.

Results: Of all 533 patients, 155 (29.1%) were diagnosed with pN0-PC and 378 (70.9%) were diagnosed with node-positive pancreatic cancer (pN1/2-PC). The 5-year survival rates of patients with pN0-PC and pN1/2-PC were 57.1% and 25.0%, respectively (p < 0.001). A multivariate analysis revealed six prognostic factors in pN0-PC: age ≥ 70 years, nonadministration of adjuvant chemotherapy, anterior serosal invasion, nerve plexus invasion, and microscopic lymphatic and venous invasions. The 5-year survival rates of patients who had pN0-PC with 0-1 risk factor, with 2-3 risk factors, and with 4-6 risk factors were 87.6%, 47.9%, and 16.4%, respectively. Survival of patients who had pN0-PC with 4-6 risk factors was comparable to that of pN1/2 patients. The diagnostic capability of metastasis-negative lymph node was unsatisfactory, with a predictive value of < 43%.

Conclusions: Although the prognosis of patients with pN0-PC was better than that of patients with pN1/2-PC, it is not satisfactory. Survival of patients who had pN0-PC with 0-1 risk factors was extremely favorable; however, survival of patients who had pN0-PC with 4-6 risk factors was similar to those with pN1/2-PC.
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http://dx.doi.org/10.1245/s10434-020-09543-xDOI Listing
April 2021

The prognostic roles of the prognostic nutritional index in patients with intraductal papillary mucinous neoplasm.

Sci Rep 2021 Jan 12;11(1):568. Epub 2021 Jan 12.

Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center Hospital, 1007, Shimo-Nagakubo, Sunto-Nagaizumi, Shizuoka, 411-8777, Japan.

The preoperative accurate diagnosis is difficult in the patients with intraductal papillary mucinous neoplasm (IPMN). The aim of the present study was to elucidate the roles of systemic inflammation responses and nutritional status indexes in IPMN. High-grade dysplasia was classified as a malignant neoplasm in the study. We retrospectively reviewed 155 patients who underwent pancreatectomy. The correlation between the clinical factors and several indexes of a systemic inflammation response and nutritional status was analyzed. Among the biomarkers, prognostic nutritional index (PNI) value of malignant IPMN patients was significantly lower than that of benign IPMN patients (P = 0.023), whereas PNI was not significant predictor for malignant IPMN. The multivariate analysis showed that a PNI < 43.5 (odds ratio [OR] 16.1, 95% CI 1.88-138.5, P = 0.011) and a carbohydrate antigen (CA) 19-9 level > 22.5 U/mL (OR 6.64, 95% CI 1.73-25.6, P = 0.006) were significant independent predictors of the presence of lymph node metastasis (LNM). Our scoring system developed based on these two factors. Patients with a score of 0 had no LNM and zero disease-related death. The present study suggested the roles of PNI on the IPMN patients who undergo curative pancreatectomy.
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http://dx.doi.org/10.1038/s41598-020-79583-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803756PMC
January 2021

Diagnostic utility of measuring serum amyloid A with a latex agglutination turbidimetric immunoassay in bovine mastitis: Comparison with haptoglobin and alpha 1 acid glycoprotein.

J Vet Med Sci 2021 Mar 29;83(2):329-332. Epub 2020 Dec 29.

School of Veterinary Medicine, Rakuno Gakuen University, 582 Bunkyodai-Midorimachi, Ebetsu, Hokkaido 069-8501, Japan.

This study established the precision and accuracy of a modified latex agglutination turbidimetric immunoassay (LATIA) reagent, and evaluated the ability of the measurement of serum amyloid A (SAA) compared to haptoglobin and α1-acid glycoprotein, which are acute phase proteins (APPs), for diagnosis of clinical mastitis. Concentrations of APPs in cows with mastitis were significantly higher than those in healthy cow. Only the plasma SAA concentration in cows with clinical mastitis (44.90 mg/l; n=15) was significantly higher than that in those with subclinical mastitis (10.70 mg/l; n=16), enabling their diagnosis in contrast to other APPs. Thus, the SAA assay using a LATIA reagent is useful in assessing mastitis severity due to its higher sensitivity and specificity than other APP assays.
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http://dx.doi.org/10.1292/jvms.20-0550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972874PMC
March 2021

The evaluation of the 8th and 7th edition of the American joint committee on cancer tumor classification for distal cholangiocarcinoma: the proposal of a modified new tumor classification.

HPB (Oxford) 2020 Dec 19. Epub 2020 Dec 19.

Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Japan.

Background: The 7th and 8th editions of the American Joint Committee on Cancer (AJCC) tumor (T) classification of distal cholangiocarcinoma (DCC), which are based on either layer or depth, may not accurately stratify patient survival.

Methods: A total of 121 patients who underwent resection for DCC between 2002 and 2016 were analyzed. The impact of the AJCC staging system on survival was examined and a new T classification was established based on independent prognostic factors.

Results: Regarding overall survival, the optimal depth of invasion (DOI) cut-off value (8 mm) was the only independent prognostic factor. Regarding the relapse-free survival (RFS), a DOI >8 mm, portal vein (PV) invasion, and duodenal or pancreatic invasion were independent prognostic factors. A new T classification was developed as follows: T1, no invasion of adjacent organs; T2, invasion of the duodenum or pancreas; T3, invasion >8 mm into the bile duct wall; and T4, invasion of the PV or arteries. There were no significant differences in RFS according to the 8th edition of the AJCC. However, significant differences were observed in the RFS between T1 and T2 and between T2 and T3.

Conclusion: A new T classification based on the layer and depth may be more feasible.
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http://dx.doi.org/10.1016/j.hpb.2020.12.001DOI Listing
December 2020

The prognostic impact of skeletal muscle status and bone mineral density for resected distal cholangiocarcinoma.

Clin Nutr 2020 Dec 15. Epub 2020 Dec 15.

Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007, Shimo-Nagakubo, Sunto-Nagaizumi, Shizuoka, 4118777, Japan.

Background & Aims: The preoperative body composition and bone mineral density (BMD) have been reported as prognostic factors for several cancers. However, the prognostic impact of the preoperative body composition and BMD for resected distal cholangiocarcinoma (DCC) remains unclear.

Methods: A total of 111 patients who underwent pancreatoduodenectomy for DCC between 2002 and 2017 were analyzed. The skeletal muscle index (SMI) and BMD were measured by preoperative computed tomography. The optimal cut-off value of the body composition and BMD were selected based on the minimum P-value obtained by the log-rank test. The prognostic significance of the preoperative body composition and BMD was investigated using multivariate analysis.

Results: The median values of the SMI (45.7 vs. 36.7 cm/m, P < 0.001) and BMD (128.5 vs. 101.0 Hounsfield units [HU], P = 0.005) in male and female were significantly different. The optimal cut-off values for the SMI were 55 cm/m in male and 36 cm/m in female, and those for the BMD were 75 HU in male and 74 HU in female. A multivariate analysis identified low SMI (hazard ratio [HR], 4.340; P = 0.044), low BMD (HR, 5.333; P < 0.001) and microscopic venous invasion (HR, 2.019; P = 0.026) as independent prognostic factors for the survival.

Conclusions: A preoperative low SMI and low BMD were independent prognostic factors for resected DCC.
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http://dx.doi.org/10.1016/j.clnu.2020.12.011DOI Listing
December 2020

Integrated Immunohistochemical Study on Small-Cell Carcinoma of the Lung Focusing on Transcription and Co-Transcription Factors.

Diagnostics (Basel) 2020 Nov 13;10(11). Epub 2020 Nov 13.

Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.

Small-cell lung cancer (SCLC) is an aggressive malignant cancer that is classified into four subtypes based on the expression of the following key transcription and co-transcription factors: ASCL1, NEUROD1, YAP1, and POU2F3. The protein expression levels of these key molecules may be important for the formation of SCLC characteristics in a molecular subtype-specific manner. We expect that immunohistochemistry (IHC) of these molecules may facilitate the diagnosis of the specific SCLC molecular subtype and aid in the appropriate selection of individualized treatments. We attempted IHC of the four key factors and 26 candidate SCLC target molecules selected from the gene expression omnibus datasets of 47 SCLC samples, which were grouped based on positive or negative results for the four key molecules. We examined differences in the expression levels of the candidate targets and key molecules. ASCL1 showed the highest positive rate in SCLC samples, and significant differences were observed in the expression levels of some target molecules between the ASCL1-positive and ASCL1-negative groups. Furthermore, the four key molecules were coordinately and simultaneously expressed in SCLC cells. An IHC study of ASCL1-positive samples showed many candidate SCLC target molecules, and IHC could become an essential method for determining SCLC molecular subtypes.
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http://dx.doi.org/10.3390/diagnostics10110949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697657PMC
November 2020

Description of the Vascular Anatomy of Livers with Absence of the Portal Bifurcation.

World J Surg 2021 Mar 9;45(3):833-840. Epub 2020 Nov 9.

Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.

Background: The absence of the portal bifurcation (APB) is a rare anatomic variation, in which the horizontal part of the left portal vein (PV) is missing. The aim of this study was to identify the vascular architecture in livers with APB.

Methods: Computed tomography data for 17,651 patients were reviewed; five patients (0.03%) were found to present with APB. The liver volume and anatomy of APB patients were compared with those of 30 patients with normal livers.

Results: All the APB patients exhibited an independent posterior branch of the PV. The intrahepatic left PV (LPV) ran through either the ventral (n = 2, 40%) or dorsal side (n = 3, 60%) of the middle hepatic vein. The frequency of medial branches diverging from the LPV was higher in patients with APB than in normal patients (p < 0.001). The left hepatic duct (LHD) ran through the inside of the left lobe along the left PV in 40% of the patients with APB, whereas in the remaining 60% of the patients with APB, the LHD ran on the outside of the liver separately from the left PV and joined the right hepatic duct. The liver volume of the left lateral section was significantly smaller (p = 0.014), and the posterior section was significantly larger (p = 0.014) in patients with APB than in patients with normal livers.

Conclusion: The unique anatomical characteristics and the positional relation of the vessels should be considered preoperatively in patients with APB.
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http://dx.doi.org/10.1007/s00268-020-05848-wDOI Listing
March 2021

INSM1 immunostaining in solid papillary carcinoma of the breast.

Pathol Int 2021 Jan 6;71(1):51-59. Epub 2020 Nov 6.

Department of Pathology and Experimental Medicine, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.

Solid papillary carcinoma (SPC) is a histological subtype of breast carcinomas. At least 50% of SPC show neuroendocrine differentiation. Insulinoma-associated protein 1 (INSM1) is a transcription factor now employed as a useful neuroendocrine marker. It is suppressed by the Notch signaling pathway in other neuroendocrine tumors. However, the usefulness of INSM1 as a neuroendocrine marker and the relationships between INSM1 and NOTCH receptors in SPC of the breast currently remain unclear. To clarify the usefulness of INSM1 as a neuroendocrine marker and the relationships between INSM1 and NOTCH receptors in SPC, we performed immunohistochemistry using 19 tissue specimens of SPC of the breast. We complementarily analyzed public RNA sequencing data on breast carcinomas. Immunohistochemical examinations revealed that the staining intensity of INSM1 was significantly higher in the neuroendocrine group than in the non-neuroendocrine group. Positive correlations were observed between INSM1 and synaptophysin (SYP), or chromogranin-A (CHGA). In all cases, NOTCH 2 and 3 were positive, while NOTCH 1 and 4 were negative. According to public RNA data analyses, there were positive correlations between INSM1 and SYP, or CHGA, and negative correlations between INSM1 and NOTCH1-3. INSM1 is useful as a diagnostic marker for SPC with neuroendocrine differentiation in the breast.
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http://dx.doi.org/10.1111/pin.13043DOI Listing
January 2021

Analysis of right-sided ligamentum teres: The novel anatomical findings and classification.

J Hepatobiliary Pancreat Sci 2021 Feb 17;28(2):221-230. Epub 2020 Nov 17.

Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan.

Background: The true anatomy of right-sided ligamentum teres (RSLT) has not been fully explained for a century. This study aimed to clarify the exact anatomy of RSLT.

Methods: The computed tomography data of 17 651 surgical patients were observed and 76 patients with RSLT, were classified into the bilateral ligamentum teres (LT) group (type A) and three RSLT groups, (B) bifurcation type, (C) trifurcation type, and (D) independent posterior branch type.

Results: Type A had double LT that connected to both the right and left sides of the umbilical portion (UP). Types B-D had a P3 + 4 rather than a left UP. Type D was anatomically different from types A-C. Upon comparing types A-C and type D, type D had a significantly smaller volume of segments 3 + 4 (P < .001), and the UP was more often on the left side. The position of the gallbladder fundus in type D was more commonly observed on the right side of the LT compared with that observed in the other types (P = .007).

Conclusions: The change in the volume of segments 3 + 4 and the extent of the RSLT shift create a false perception that the gallbladder changes the position.
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http://dx.doi.org/10.1002/jhbp.856DOI Listing
February 2021

Identifying specific Notch1 target proteins in lung carcinoma cells.

Histol Histopathol 2021 Jan 23;36(1):69-76. Epub 2020 Oct 23.

Department of Pathology and Experimental Medicine, Kumamoto University, Graduate School of Medical Sciences, Kumamoto, Japan.

Background: The Notch signaling pathway has different roles in many human neoplasms, being either tumor-promoting or anti-proliferative. In addition, Notch signaling in carcinogenesis can be tissue dependent. The aim of the current study is to elucidate the relation between Notch1 protein expression in lung cancer cells and the following Notch related proteins: Hes1, c-Myc, Jagged1 and Jagged2.

Methods: Notch1 and its related proteins were detected in human lung cancer cell lines and in 54 surgically resected different lung carcinoma tissues. Then, we used small interfering RNA (siRNA) technology, to down-regulate the expression of Notch1 in H69AR and SBC3 small cell lung carcinoma (SCLC) cells. Also, we transfected venus Notch1 intracellular domain (v.NICD) plasmid into human SCLC lines; H69.

Results: The expression of Hes1, c-Myc and Jagged2 is affected by Notch1 in SCLC.

Conclusion: There is a strong association between the expression of Notch1 protein and the expression of Hes1, c-Myc and Jagged2 proteins, which could aid in better understanding tumorigenesis in SCLC.
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http://dx.doi.org/10.14670/HH-18-271DOI Listing
January 2021

The influence of familial pancreatic cancer on postoperative outcome in pancreatic cancer: relevance to adjuvant chemotherapy.

J Gastroenterol 2021 Jan 22;56(1):101-113. Epub 2020 Oct 22.

Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka Cancer Center Hospital, 1007, Shimo-Nagakubo, Sunto-Nagaizumi, Shizuoka, 411-8777, Japan.

Background: Familial pancreatic cancer (FPC) is defined as a family in which at least two first-degree relatives have pancreatic cancer (PC). The prognostic significance of PC in an FPC family after surgery is not fully understood.

Methods: This was a retrospective study of 427 patients who underwent pancreatectomy for pancreatic ductal adenocarcinoma between January 2008 and December 2016. PC patients who also had at least one first-degree relative with PC were defined as FPC patients. The associations between recurrence and clinicopathological characteristics were analyzed for both FPC and non-FPC patients.

Results: FPC patients accounted for 31 of the 427 (7.3%) patients. Recurrence occurred in 72.1% of the total cohort and in 87.1% of the 31 FPC patients. Multivariate analysis showed that being an FPC patient was an independent predictor for relapse-free survival (RFS) (hazard ratio [HR] 1.52, P = 0.038). Although univariate analysis revealed that being an FPC patient was significantly associated with poorer overall survival (OS) (P < 0.001), multivariate analysis showed that being an FPC patient was not an independent predictor for OS (P = 0.164). Dichotomization of the 427 patients into those who received (n = 317: 17 FPC and 300 non-FPC patients) and did not receive (n = 110: 14 FPC and 96 non-FPC patients) adjuvant chemotherapy revealed that being an FPC patient was an independent predictor for RFS (HR 2.50, P < 0.001) and OS (HR 2.30, P = 0.003) only for patients who received adjuvant chemotherapy.

Conclusions: This study has shown that being an FPC patient is a significant prognostic indicator for PC patients who undergo resection and receive adjuvant chemotherapy.
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http://dx.doi.org/10.1007/s00535-020-01730-7DOI Listing
January 2021

Prognostic Impact of Paraaortic Lymph Node Metastasis in Extrahepatic Cholangiocarcinoma.

World J Surg 2021 Feb 20;45(2):581-589. Epub 2020 Oct 20.

Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007, Shimo-Nagakubo, Sunto- Nagaizumi, Shizuoka, 4118777, Japan.

Background: Surgical resection in patients with extrahepatic cholangiocarcinoma (EHCC) with paraaortic lymph node metastasis (PALNM) remains controversial. The objective of this study was to investigate the prognostic impact of PALNM in resected EHCC.

Methods: The present retrospective study included 410 patients, including 16 patients with PALNM, who underwent surgical resection of EHCC between September 2002 and December 2018. These were compared to 9 patients in whom EHCC was not resected due to PALNM. The clinicopathological features and survival outcomes were investigated to identify the prognostic factors in resected EHCC.

Results: The overall survival in the resected patients with PALNM was significantly better than that in unresected patients (median survival time [MST] 33.7 vs. 16.7 months, p=0.009) and was not significantly worse than that of patients with regional lymph node metastasis (LNM) (MST 33.7 vs 36.0 months, p=0.278). The multivariate analysis identified age > 70 years, male sex, tumor location (perihilar), residual tumor status, histological grade, microscopic venous invasion, and regional LNM as independent prognostic factors.

Conclusions: There was no significant difference in survival between the resected patients with PALNM and patients with regional LNM, and PALNM was not a significant prognostic factor in the multivariate analysis. Surgical resection may be considered an acceptable approach for EHCC with PALNM in selected patients.
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http://dx.doi.org/10.1007/s00268-020-05834-2DOI Listing
February 2021

Middle segment-preserving pancreatectomy for multifocal pancreatic ductal adenocarcinoma located in the head and tail of the pancreas: a case report.

J Surg Case Rep 2020 Oct 7;2020(10):rjaa383. Epub 2020 Oct 7.

Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan.

A 77-year-old woman with a solitary existence was referred to our hospital for the treatment of pancreatic tumors. Computed tomography revealed an 18-mm mass in the pancreatic head that had invaded the right side of the superior mesenteric vein (SMV) and a 32-mm mass in the pancreatic tail. We performed middle segment-preserving pancreatectomy (MSPP) with SMV resection and reconstruction. The TNM classifications were T2, N1, M0, stage IIB in the pancreatic head, and T2, N0, M0, stage IB in the pancreatic tail, respectively. Postoperatively, the blood glucose was well controlled using only hypoglycemic drug, and insulin preparation was not necessary. No fatty diarrhea was found using a pancreatic enzyme supplement. After 9 months of follow-up, no recurrence was found. MSPP for pancreatic head and tail carcinomas seemed acceptable for both preserving the postoperative quality of life and ensuring curative resection especially in elderly patient with a solitary existence.
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http://dx.doi.org/10.1093/jscr/rjaa383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540631PMC
October 2020

Laparoscopic repeat liver resection for hepatic epithelioid hemangioendothelioma.

Surg Case Rep 2020 Oct 1;6(1):254. Epub 2020 Oct 1.

Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.

Background: Optimal treatment for patients with hepatic epithelioid hemangioendothelioma (HEHE) remains unclear. Laparoscopic repeat liver resection (LR) is a minimally invasive and potentially effective surgical option for multiple HEHEs.

Case Presentation: A 42-year-old woman with no relevant history was admitted for multiple liver tumors. Six tumors were observed on T2-weighted magnetic resonance imaging (MRI) including one in S2, two in S3, two in S7, and one in S8. Pathological evaluation of percutaneous tumor biopsy tissue suggested a diagnosis of HEHE and laparoscopic LR was planned. The procedure began with partial resection of S7 and partial resection of S8 and left lateral sectionectomy were performed. Another tumor was found intraoperatively on the surface of S6, necessitating removal by partial resection. Pathological evaluation of the resected tumor tissue from all seven tumors concurred with that of the preoperative biopsy. The patient was discharged on postoperative day 6 without any complications. A follow-up MRI 15 months after the primary surgery revealed one tumor each in S4, S6, and S8. Laparoscopic repeat LR was performed. The patient was discharged on postoperative day 5 without any complications. All three recurrent tumors were pathologically confirmed as HEHEs.

Conclusions: We successfully treated primary and recurrent HEHEs with laparoscopic LR, which is a reasonable minimally invasive procedure considering the possibility of multiple courses of liver surgery in patients with HEHE.
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http://dx.doi.org/10.1186/s40792-020-01036-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530154PMC
October 2020

The Prognostic Relevance of the Number and Location of Positive Lymph Nodes for Ampulla of Vater Carcinoma.

World J Surg 2021 Jan 9;45(1):270-278. Epub 2020 Sep 9.

Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Sunto-Nagaizumi, Shizuoka, 4118777, Japan.

Background: Lymph node metastasis (LNM) has been regarded as one of the prognostic factors in patients with ampulla of Vater carcinoma (AC). However, the consensus about an optimal cutoff value of the number of LNMs and the definition of the regional lymph nodes (RLNs) has not been achieved.

Methods: This study included 114 consecutive patients who underwent pancreatoduodenectomy for AC between January 2002 and March 2019.

Results: The minimum p value approach for the greatest difference in the overall survival classified the number of LNM into none (N0, n = 66), from 1 to 2 (N1, n = 32), and ≥3 LNM (N2, n = 11) (p = 0.004). Distant LNM was defined as M1 (n = 5). Significant differences in relapse-free survival (RFS) were found between N0 and N1 (p < 0.001), N1 and N2 (p = 0.047), and N1 and M1 (p = 0.044) but not between N2 and M1 (p = 0.683). Moreover, the patients with regional LNM were classified into two groups: Np group (n = 35, LNM only in pancreatic head region) and Nd group (n = 8, LNM in other regional location). Significant differences in the RFS were found between N0 and Np (p < 0.001), Np and Nd (p = 0.004), and Np and M1 (p = 0.033) but not between Nd and M1 (p = 0.883). A Cox proportional hazards analysis for RFS revealed that ≥ 3 LNMs (hazards ratio [HR], 3.22) and LNM except for pancreatic head region (HR, 4.27) were individually independent worse prognostic factors.

Conclusions: ≥3 LNMs and regional LNM except for pancreatic head region were associated with poor prognosis comparable to that of the patients with M1.
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http://dx.doi.org/10.1007/s00268-020-05770-1DOI Listing
January 2021

Reconsidering the Optimal Regional Lymph Node Station According to Tumor Location for Pancreatic Cancer.

Ann Surg Oncol 2021 Mar 29;28(3):1602-1611. Epub 2020 Aug 29.

Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan.

Background: A consensus regarding the optimal extent of lymph node dissection for pancreatic cancer has not yet been achieved. The purpose of this study was to evaluate the efficacy of lymph node dissection according to the location for pancreatic cancer.

Methods: A total of 495 patients diagnosed with invasive ductal carcinoma of the pancreas who had undergone a pancreatectomy between October 2002 and December 2015 were analyzed. The efficacy index (EI) was calculated for each lymph node station via multiplication of the frequency of metastasis to the station and the 5-year survival rate of the patients with metastasis to that station.

Results: For pancreatic head (Ph) tumors, mesocolon lymph nodes had a high EI, although not regional. For pancreatic body (Pb) tumors, peri-Ph lymph nodes had a high EI, although not regional. For pancreatic tail (Pt) tumors, lymph nodes along the celiac axis and common hepatic artery had a zero EI, although regional. When the Ph was segmented into the pancreatic neck (Ph-neck), uncinate process (Ph-up), and periampullary regions, hepatoduodenal ligament lymph nodes had a zero EI for Ph-up, although regional; the mesojejunum lymph node also had a zero EI, even for Ph-up, regardless of a high incidence of metastasis. Regarding lymph node recurrence after surgery, recurrence was most frequently found at the peri-Ph lymph node (12%) in patients with Pb tumors who had undergone a distal pancreatectomy.

Conclusions: The optimal extent of lymph node dissection should be estimated in regard to the tumor location.
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http://dx.doi.org/10.1245/s10434-020-09066-5DOI Listing
March 2021

The clinical impact and risk factors of latent pancreatic fistula after pancreatoduodenectomy.

J Hepatobiliary Pancreat Sci 2020 Dec 18;27(12):1002-1010. Epub 2020 Sep 18.

Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan.

Background: Latent pancreatic fistula (LPF) is difficult to diagnose during the early postoperative phase because of initially normal drain fluid amylase (DFA) levels. The present study investigated the clinical significance and risk factors of LPF after pancreatoduodenectomy.

Methods: A total of 662 patients who underwent pancreatoduodenectomy between 2010 and 2018 were retrospectively analyzed. LPF was defined as pancreatic fistula that developed later regardless of initially low DFA levels.

Results: Among the 372 patients with DFA ≤375 U/L (three times the upper limit for serum) on postoperative day (POD) 3, LPF occurred in 37 (10%). The rates of postoperative hemorrhaging (11% vs 1.5%), intraabdominal abscess (57% vs 7.2%) and reintervention (46% vs 2.7%) were significantly higher in the patients with LPF than in those without LPF. A multivariate analysis revealed that a body mass index ≥25 kg/m , a non-combined portal vein resection, a DFA on POD 1 ≥650 U/L and a C-reactive protein level on POD 3 ≥11 mg/dL were independent risk factors for LPF.

Conclusions: Latent pancreatic fistula was significantly associated with severe complications and worse outcomes after pancreatoduodenectomy. Early drain removal may be unfavorable for patients with some of these risk factors.
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http://dx.doi.org/10.1002/jhbp.820DOI Listing
December 2020

Prognostic impact of abutment to the branches of the superior mesenteric artery in borderline resectable pancreatic cancer.

Langenbecks Arch Surg 2020 Nov 27;405(7):939-947. Epub 2020 Aug 27.

Divisions of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Sunto-Nagaizumi, Shizuoka, 4118777, Japan.

Purpose: The clinical impact of abutment to an artery and its branch on resectability and prognosis in patients with borderline resectable pancreatic cancer is unclear.

Methods: Patients diagnosed with borderline resectable pancreatic cancer due to artery abutment between April 2012 and December 2018 were enrolled. Contact between arteries and the tumour was assessed by computed tomography (CT).

Results: A primary lesion was resected in 63 patients (R group) and unresected in 19 patients (UR group). Overall survival (OS) was worse in the UR group than in the R group (P < 0.001). Multivariate analysis showed that abutment to the superior mesenteric artery (SMA) branches (P = 0.001) was an independent predictor of poor OS after surgery. Regarding the initial recurrence pattern, abutment to the SMA branches was significantly associated with high incidence of distant metastasis (P < 0.001). According to the most distal SMA branch attached on CT, significant differences in RFS were found between absent-J1A (P = 0.017), J2A-J3A (P = 0.0313) and J3A-middle colic artery (MCA, P = 0.0476) but not between J1A-J2A (P = 0.8207). Significant prognostic differences in OS after initiation of the treatment were found between absent-J1A/J2A (P = 0.006) and J1A/J2A-J3A/MCA (P = 0.033) but not between J3A/MCA-UR (P = 0.494).

Conclusion: Abutment to the SMA branches was associated with high incidence of distant metastasis after resection and a poor survival. Especially, abutment to the J3A or MCA was associated with poor prognosis comparable with that of the UR group.
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http://dx.doi.org/10.1007/s00423-020-01970-4DOI Listing
November 2020

Distinct transcriptional programs of SOX2 in different types of small cell lung cancers.

Lab Invest 2020 12 14;100(12):1575-1588. Epub 2020 Aug 14.

Department of Pathology and Experimental Medicine, Graduate School of Medical Science, Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto, 860-8556, Japan.

SOX2 is recognized as an oncogene in human small cell lung cancer (SCLC), which is an aggressive neuroendocrine (NE) tumor. However, the role of SOX2 in SCLC is not completely understood, and strategies to selectively target SOX2 in SCLC cells remain elusive. Here, we show, using next-generation sequencing, that SOX2 expressed in the ASCL1-high SCLC (SCLC-A) subtype cell line is dependent on ASCL1, which is a lineage-specific transcriptional factor, and is involved in NE differentiation and tumorigenesis. ASCL1 recruits SOX2, which promotes INSM1 and WNT11 expression. Immunohistochemical studies revealed that SCLC tissue samples expressed SOX2, ASCL1, and INSM1 in 18 out of the 30 cases (60%). Contrary to the ASCL1-SOX2 signaling axis controlling SCLC biology in the SCLC-A subtype, SOX2 targets distinct genes such as those related to the Hippo pathway in the ASCL1-negative, YAP1-high SCLC (SCLC-Y) subtype. Although SOX2 knockdown experiments suppressed NE differentiation and cell proliferation in the SCLC-A subtype, they did not sufficiently impair the growth of the SCLC-Y subtype cell lines in vitro and ex vivo. The present results support the importance of the ASCL1-SOX2 axis as a main subtype of SCLC, and suggest the therapeutic potential of targeting the ASCL1-SOX2 axis.
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http://dx.doi.org/10.1038/s41374-020-00479-0DOI Listing
December 2020

Intraductal tubulopapillary neoplasms with rupture of the distal main pancreatic duct: a case report.

Surg Case Rep 2020 Aug 14;6(1):210. Epub 2020 Aug 14.

Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimo-Nagakubo, Sunto-Nagaizumi, Shizuoka, 411-8777, Japan.

Background: Intraductal tubulopapillary neoplasm (ITPN) is a rare and newly described entity defined as an intraductal, grossly visible, tubule-forming epithelial neoplasm with high-grade dysplasia and ductal differentiation without overt production of mucin. Because of its rarity, the clinical and molecular aspects of ITPN have not been fully investigated.

Case Presentation: A 73-year-old woman presented to a local hospital with epigastric discomfort and pain. Abdominal multidetector-row computed tomography (MDCT) revealed a 2.5-cm hypovascular tumor in the pancreatic body with distal pancreatic duct dilatation and a slightly low-density area spreading over the ventral side of the pancreatic body. Endoscopic ultrasonography and fine-needle biopsy of the tumor revealed adenocarcinoma of the pancreas. She was referred to our hospital 2 months later. MDCT performed at our hospital showed no significant change in the tumor size or pancreatic duct dilatation. However, the low-density area at the ventral side of the pancreas had shrunk; therefore, this finding was considered to have been an inflammatory change. Under a preoperative diagnosis of resectable pancreatic ductal adenocarcinoma, distal pancreatectomy was performed. The final diagnosis was ITPN with associated invasive carcinoma. Macroscopically and microscopically, the main pancreatic duct (MPD) had ruptured at the distal side of the tumor, and the fistula connected the MPD and extrapancreatic scar tissue.

Conclusions: ITPN with rupture of the pancreatic duct is extremely rare. In the present case, a sudden increase in the pancreatic duct internal pressure or acute inflammation likely caused the rupture of the MPD.
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http://dx.doi.org/10.1186/s40792-020-00972-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427828PMC
August 2020

Single administration of avelumab induced a complete response in thyroid transcription factor 1-positive combined Merkel cell carcinoma.

J Dermatol 2020 Nov 13;47(11):1317-1321. Epub 2020 Aug 13.

Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

Merkel cell carcinoma (MCC) is an aggressive neoplasm and patients with metastasis have poor survival outcomes. Recently, avelumab, an anti-programmed death ligand 1 (PD-L1) immune checkpoint inhibitor, was approved for first-line treatment in patients with metastatic MCC. While the administration interval of avelumab is every 2 weeks, the durable effect of a single administration of avelumab is unknown. Additionally, the effect of avelumab in pure MCC or combined MCC concurrent with non-MCC histology has not been fully elucidated. Herein, we report a case of combined MCC concurrent with squamous cell carcinoma; the patient had a complete response after a single administration of avelumab. Although the levels of avelumab were outside the detection limit within 12 weeks, a remarkable efficacy remained for more than 28 weeks after administration. Immunohistochemical analyses revealed that the expression of PD-L1 and Merkel cell polyomavirus large T antigen was almost negative or only partial in the primary tumor lesion of this patient. Conversely, thyroid transcription factor 1 (TTF-1) expression was positive in the primary MCC lesion, which is consistent with a previous report that combined MCC is positive for TTF-1 expression. In conclusion, this case study presents a rare case of TTF-1-positive combined MCC showing complete response after a single administration of avelumab.
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http://dx.doi.org/10.1111/1346-8138.15543DOI Listing
November 2020

Use of preoperative controlling nutritional status (CONUT) score as a better prognostic marker for distal cholangiocarcinoma after pancreatoduodenectomy.

Surg Today 2021 Mar 6;51(3):358-365. Epub 2020 Aug 6.

Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Shizuoka, Sunto-gun, 411-8777, Japan.

Purpose: The controlling nutritional status (CONUT) score can be easily calculated from the serum albumin concentration, total cholesterol concentration, and total lymphocyte count. The study aim was to assess the preoperative prognostic factors for the overall survival (OS) of distal cholangiocarcinoma (DCC) following pancreatoduodenectomy (PD) and to demonstrate the utility of the CONUT score.

Methods: A total of 149 consecutive patients who underwent PD for DCC between September 2002 and December 2016 were divided into a low-CONUT (LC) group (CONUT scores ≤ 2) and a high-CONUT (HC) group (CONUT scores ≥ 3). The clinicopathological characteristics and OS of the patients were evaluated retrospectively. Prognostic factors of DCC were identified by multivariate analyses.

Results: The LC and HC groups included 113 and 36 patients, respectively. The OS was better in the LC group than in the HC group (median survival time and 5 year survival rate: 82 months and 56.8% vs. 38 months and 27.6%, P = 0.005). Multivariate analyses for the OS in all patients showed that the tumor differentiation, perineural invasion, residual tumor status, portal vein resection, blood transfusion, and preoperative CONUT score ≥ 3 were independently associated with a poor survival.

Conclusion: The CONUT score may be a useful preoperative factor for predicting the long-term survival in patients with DCC.
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http://dx.doi.org/10.1007/s00595-020-02098-0DOI Listing
March 2021

Adjuvant chemoradiotherapy for positive hepatic ductal margin on cholangiocarcinoma.

Ann Gastroenterol Surg 2020 Jul 15;4(4):455-463. Epub 2020 May 15.

Division of Gastrointestinal Oncology Shizuoka Cancer Center Shizuoka Japan.

Aim: This study evaluated the effects of postoperative adjuvant chemoradiotherapy (A-CRT) for positive hepatic ductal margin (HM+) in extrahepatic cholangiocarcinoma (EHCC).

Methods: Patients with EHCC who underwent surgical resection between 2002 and 2014 were included in this retrospective study. For patients with HM+, A-CRT was conducted. The clinical effect of A-CRT for HM+ on the survival and recurrence and prognostic factors of EHCC was reviewed.

Results: Among 340 patients, the hepatic ductal margin was negative in 296 and positive in 44. Of the 44 patients with HM+, 22 received postoperative A-CRT, and 22 did not. Hepatic stump recurrence occurred in 19 patients. The incidence was significantly higher in patients with HM+ (20%, 9/44) than in those with negative hepatic ductal margin (HM-) (3%, 10/296) ( < .001). Among the patients with HM+, the incidence was almost identical between the patients with and without A-CRT: 23% (5/22) in HM+/CRT- and 18% (4/22) in HM+/CRT+ patients ( = .999). The median survival time was 49 months in HM-, 43 months in HM+/CRT-, and 49 months in HM+/CRT+ patients. The differences were not significant among the groups. A multivariate analysis revealed CA 19-9 ≥ 300 U/mL, combined vascular resection, histologic grade G2/G3, and lymph node metastasis to be significant prognostic factors. However, the performance of postoperative A-CRT did not contribute to prolonging survival.

Conclusion: A-CRT for HM+ in patients with EHCC did not affect the survival or stump recurrence.
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http://dx.doi.org/10.1002/ags3.12345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382438PMC
July 2020

Kiss1R Identification and Biodistribution Analysis Employing a Western Ligand Blot and Ligand-Derivative Stain with a FITC-Kisspeptin Derivative.

ChemMedChem 2020 Sep 20;15(18):1699-1705. Epub 2020 Aug 20.

Department of Pathology and Experimental Medicine Graduate School of Medical Sciences, Kumamoto University, Honjyo 1-1-1, Chyuo-ku, Kumamoto, 860-855, Japan.

It is not always easy to establish specific antibodies against receptors. Most receptors are hydrophobic and have complicated three-dimensional structures, making them difficult to use as immunogens. Thus, we developed receptor detection methods with a fluorescein-labeled ligand as an antibody alternative, which we referred to as a western ligand blot (WLB) and ligand derivative stain (LDS). Kisspeptin receptor (Kiss1R) was detected by its ligand. Kiss1R expression was confirmed in eight human cell lines by the WLB and in four pathological tissues by the LDS. Next, Kiss1R was stained by LDS in organs, revealing Kiss1R expression by [ Ga]Ga-DOTA-kisspeptin 10 accumulation. As a result, Kiss1R-expressing cells in each organ could be stained with fluorescein-labeled kisspeptin 14 instead of an antibody and observed by light microscopy. The combination of the WLB and LDS allows identification of receptors in tissues, which can be readily applied to target receptor detection by a synthetic ligand derivative.
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http://dx.doi.org/10.1002/cmdc.202000356DOI Listing
September 2020